Prostate cancer is the most common type of cancer found in American men, other than skin cancer. Prostate cancer is the second leading cause of cancer death in men. (Lung cancer is the first.) One man in 6 will get prostate cancer during his lifetime. And one man in 35 will die of this disease. More than 2 million men in the United States who have had prostate cancer at some point are still alive today. In 2009, there were over 190,000 new cases of prostate cancer, and over 27,000 deaths from prostate cancer (American Cancer Society).
Prostate cancer has been treated with hormonal therapy, surgical therapy, radiation therapy, or chemotherapy, or combinations thereof. Hormonal therapy suppresses the production or activity of androgen which is involved in the growth of prostate cancer. The hormonal therapy is carried out by removing testicles that produce androgen, or by administering an LH-RH analog that acts on the pituitary gland and reduces the level of testosterone, an estrogen preparation, or an anti-androgen agent, etc. Hormonal therapy is the only therapeutic method available for treating advanced prostate cancer. However, many advanced prostate cancer patients acquire hormone resistance several years after starting hormonal therapy, and they struggle with the treatment.
Expression of E2F-1, an “activating” E2F transcription factor, is low in benign and localized prostate cancer, modestly elevated in involved lymph nodes and highly elevated in metastatic tissues from patients with hormone refractory prostate cancer. E2F-1, compared to other E2Fs, has a unique role in that it triggers both apoptosis and proliferation via activation of downstream target genes. Target genes activated by E2F include dihydrofolate reductase (DHFR), thymidylate synthase (TS) and thymidine kinase (DeGregori et al, 2006). Recent evidence also shows E2F-1 can activate the miR-106b-25 cluster, via inhibition of TGFβ interference with the expression of p21 and BCL2L11(BIM) (Petrocca et al, 2008). Therefore in cells with dysregulated and high expression of E2F-1, which drives tumor growth, inhibition of E2F1 expression leads to cell death. Furthermore, the downstream target genes, DHFR and TS are decreased by E2F1 inhibition, allowing the potential for synergistic cell kill with an inhibitor of E2F-1 along with inhibitors of these enzymes, (e.g. methotrexate and 5-fluorouracil). Of interest, MTX and 5 FU are less efficacious in prostate cancer treatment as high E2F-1 levels increase resistance to these drugs (Li et al 1995). Decreasing DHFR and TS expression may increase sensitivity to these inhibitors. Accordingly, E2F levels are elevated in hormone refractory prostate cancer and its role in cellular proliferation makes the E2F-1 transcription factor an attractive target for therapy.
Accordingly strategies for inhibiting E2F-1 function using peptides have been suggested. There is precedent for this approach and several groups have devised strategies based on blocking the DNA binding function of the E2Fs. The main approaches reported to inhibit the function of E2Fs are: a) using dominant negative E2Fs or using antisense oligonucleotides to inhibit E2F synthesis, or decoys (Isizaki et al, 1996; Mann et al, 1999; Kaelin 2003), or, b) using decoy dominant inhibitory proteins or peptides that interfere with the E2F-DNA interaction (Bandera et al, 1997; Fabbrizzio et al, 1999; Ma et al, 2008). However none of these strategies have been completely satisfactory and there remains a need for additional treatment strategies.
Thus, there is a need in the art for effective therapeutic methods for treating prostate cancer that has acquired resistance to the hormonal therapy.